RNA interference (RNAi) has the potential to revolutionize treatment of dominant genetic disorders. Small inhibitory RNAs (siRNAs) are highly potent and selective, demonstrating remarkable single-nucleotide specificity. Clinical trials using siRNAs are currently underway for a few indications including age-related macular degeneration and respiratory syncitial virus infection. No siRNA treatment of skin disorders has been introduced into the clinic to date. This proposal is for a clinical trial for pachyonychia congenita (PC), an ultra-rare genetic skin disorder, using TD101. TD101 is a siRNA that specifically and potently targets a single nucleotide mutation in the gene encoding keratin 6a (K6a), resulting in a pathogenic amino acid change of asparagine to lysine. The major complaint of PC patients is the debilitating, painful callusing and blistering which occurs on or near the pressure points of the feet. It is these defined regions on the soles of the feet of K6a N171K mutation carriers that are targeted for local siRNA treatment in the proposed clinical trial. All known, eligible and willing U.S. patients with the K6a N171K mutation will be treated in a Phase 1b clinical trial. This trial is the "first-in-man" for siRNA treatment in skin. Although pachyonychia congenita is a rare disease, the nature of the disorder makes it an ideal prototype skin disorder (defined mutations with expression in limited, defined areas) for an initial siRNA clinical trial and the lessons learned should be readily generalized to other skin disorders including rare disorders such as epidermolysis bullosa simplex.